Human adolescent brain similarity development is different for paralimbic versus neocortical zones.

Adolescent development of human brain structural and functional networks is increasingly recognized as fundamental to emergence of typical and atypical adult cognitive and emotional proodal magnetic resonance imaging (MRI) data collected from N [Formula: see text] 300 healthy adolescents (51%; female; 14 to 26 y) each scanned repeatedly in an accelerated longitudinal design, to provide an analyzable dataset of 469 structural scans and 448 functional MRI scans. We estimated the morphometric similarity between each possible pair of 358 cortical areas on a feature vector comprising six macro- and microstructural MRI metrics, resulting in a morphometric similarity network (MSN) for each scan. Over the course of adolescence, we found that morphometric similarity increased in paralimbic cortical areas, e.g., insula and cingulate cortex, but generally decreased in neocortical areas, and these results were replicated in an independent developmental MRI cohort (N [Formula: see text] 304). Increasing hubness of paralimbic nodes in MSNs was associated with increased strength of coupling between their morphometric similarity and functional connectivity. Decreasing hubness of neocortical nodes in MSNs was associated with reduced strength of structure-function coupling and increasingly diverse functional connections in the corresponding fMRI networks. Neocortical areas became more structurally differentiated and more functionally integrative in a metabolically expensive process linked to cortical thinning and myelination, whereas paralimbic areas specialized for affective and interoceptive functions became less differentiated, as hypothetically predicted by a developmental transition from periallocortical to proisocortical organization of the cortex. Cytoarchitectonically distinct zones of the human cortex undergo distinct neurodevelopmental programs during typical adolescence.

Goal-directed learning is multidimensional and accompanied by diverse and widespread changes in neocortical signaling.

New tasks are often learned in stages with each stage reflecting a different learning challenge. Accordingly, each learning stage is likely mediated by distinct neuronal processes. And yet, most rodent studies of the neuronal correlates of goal-directed learning focus on individual outcome measures and individual brain regions. Here, we longitudinally studied mice from naïve to expert performance in a head-fixed, operant conditioning whisker discrimination task. In addition to tracking the primary behavioral outcome of stimulus discrimination, we tracked and compared an array of object-based and temporal-based behavioral measures. These behavioral analyses identify multiple, partially overlapping learning stages in this task, consistent with initial response implementation, early stimulus-response generalization, and late response inhibition. To begin to understand the neuronal foundations of these learning processes, we performed widefield Ca2+ imaging of dorsal neocortex throughout learning and correlated behavioral measures with neuronal activity. We found distinct and widespread correlations between neocortical activation patterns and various behavioral measures. For example, improvements in sensory discrimination correlated with target stimulus evoked activations of response-related cortices along with distractor stimulus evoked global cortical suppression. Our study reveals multidimensional learning for a simple goal-directed learning task and generates hypotheses for the neuronal modulations underlying these various learning processes.

Developmental Cajal-Retzius cell death contributes to the maturation of layer 1 cortical inhibition and somatosensory processing.

The role of developmental cell death in the formation of brain circuits is not well understood. Cajal-Retzius cells constitute a major transient neuronal population in the mammalian neocortex, which largely disappears at the time of postnatal somatosensory maturation. In this study, we used mouse genetics, anatomical, functional, and behavioral approaches to explore the impact of the early postnatal death of Cajal-Retzius cells in the maturation of the cortical circuit. We find that before their death, Cajal-Retzius cells mainly receive inputs from layer 1 neurons, which can only develop their mature connectivity onto layer 2/3 pyramidal cells after Cajal-Retzius cells disappear. This developmental connectivity progression from layer 1 GABAergic to layer 2/3 pyramidal cells regulates sensory-driven inhibition within, and more so, across cortical columns. Here we show that Cajal-Retzius cell death prevention leads to layer 2/3 hyper-excitability, delayed learning and reduced performance in a multi-whisker-dependent texture discrimination task.

Modulation of large rhythmic depolarizations in human large basket cells by norepinephrine and acetylcholine.

Rhythmic brain activity is critical to many brain functions and is sensitive to neuromodulation, but so far very few studies have investigated this activity on the cellular level in vitro in human brain tissue samples. This study reveals and characterizes a novel rhythmic network activity in the human neocortex. Using intracellular patch-clamp recordings of human cortical neurons, we identify large rhythmic depolarizations (LRDs) driven by glutamate release but not by GABA. These LRDs are intricate events made up of multiple depolarizing phases, occurring at ~0.3 Hz, have large amplitudes and long decay times. Unlike human tissue, rat neocortex layers 2/3 exhibit no such activity under identical conditions. LRDs are mainly observed in a subset of L2/3 interneurons that receive substantial excitatory inputs and are likely large basket cells based on their morphology. LRDs are highly sensitive to norepinephrine (NE) and acetylcholine (ACh), two neuromodulators that affect network dynamics. NE increases LRD frequency through ß-adrenergic receptor activity while ACh decreases it via M4 muscarinic receptor activation. Multi-electrode array recordings show that NE enhances and synchronizes oscillatory network activity, whereas ACh causes desynchronization. Thus, NE and ACh distinctly modulate LRDs, exerting specific control over human neocortical activity.

Transient enhancement of stimulus-evoked activity in neocortex during sensory learning.

Synaptic potentiation has been linked to learning in sensory cortex, but the connection between this potentiation and increased sensory-evoked neural activity is not clear. Here, we used longitudinal in vivo Ca2+ imaging in the barrel cortex of awake mice to test the hypothesis that increased excitatory synaptic strength during the learning of a whisker-dependent sensory-association task would be correlated with enhanced stimulus-evoked firing. To isolate stimulus-evoked responses from dynamic, task-related activity, imaging was performed outside of the training context. Although prior studies indicate that multiwhisker stimuli drive robust subthreshold activity, we observed sparse activation of L2/3 pyramidal (Pyr) neurons in both control and trained mice. Despite evidence for excitatory synaptic strengthening at thalamocortical and intracortical synapses in this brain area at the onset of learning-indeed, under our imaging conditions thalamocortical axons were robustly activated-we observed that L2/3 Pyr neurons in somatosensory (barrel) cortex displayed only modest increases in stimulus-evoked activity that were concentrated at the onset of training. Activity renormalized over longer training periods. In contrast, when stimuli and rewards were uncoupled in a pseudotraining paradigm, stimulus-evoked activity in L2/3 Pyr neurons was significantly suppressed. These findings indicate that sensory-association training but not sensory stimulation without coupled rewards may briefly enhance sensory-evoked activity, a phenomenon that might help link sensory input to behavioral outcomes at the onset of learning.

Sex-specific resilience of neocortex to food restriction.

Mammals have evolved sex-specific adaptations to reduce energy usage in times of food scarcity. These adaptations are well described for peripheral tissue, though much less is known about how the energy-expensive brain adapts to food restriction, and how such adaptations differ across the sexes. Here, we examined how food restriction impacts energy usage and function in the primary visual cortex (V1) of adult male and female mice. Molecular analysis and RNA sequencing in V1 revealed that in males, but not in females, food restriction significantly modulated canonical, energy-regulating pathways, including pathways associated waith AMP-activated protein kinase, peroxisome proliferator-activated receptor alpha, mammalian target of rapamycin, and oxidative phosphorylation. Moreover, we found that in contrast to males, food restriction in females did not significantly affect V1 ATP usage or visual coding precision (assessed by orientation selectivity). Decreased serum leptin is known to be necessary for triggering energy-saving changes in V1 during food restriction. Consistent with this, we found significantly decreased serum leptin in food-restricted males but no significant change in food-restricted females. Collectively, our findings demonstrate that cortical function and energy usage in female mice are more resilient to food restriction than in males. The neocortex, therefore, contributes to sex-specific, energy-saving adaptations in response to food restriction.

Histamine in the neocortex: Towards integrating multiscale effectors.

Histamine is a modulatory neurotransmitter, which has received relatively less attention in the central nervous system than other neurotransmitters. The functional role of histamine in the neocortex, the brain region that controls higher-order cognitive functions such as attention, learning and memory, remains largely unknown. This article focuses on the emerging roles and mechanisms of histamine release in the neocortex. We describe gaps in current knowledge and propose the application of interdisciplinary tools to dissect the detailed multiscale functional logic of histaminergic action in the neocortex ranging from sub-cellular, cellular, dendritic and synaptic levels to microcircuits and mesoscale effects.

Selective recruitment of the cerebellum evidenced by task-dependent gating of inputs.

Functional magnetic resonance imaging (fMRI) studies have documented cerebellar activity across a wide array of tasks. However, the functional contribution of the cerebellum within these task domains remains unclear because cerebellar activity is often studied in isolation. This is problematic, as cerebellar fMRI activity may simply reflect the transmission of neocortical activity through fixed connections. Here, we present a new approach that addresses this problem. Rather than focus on task-dependent activity changes in the cerebellum alone, we ask if neocortical inputs to the cerebellum are gated in a task-dependent manner. We hypothesize that input is upregulated when the cerebellum functionally contributes to a task. We first validated this approach using a finger movement task, where the integrity of the cerebellum has been shown to be essential for the coordination of rapid alternating movements but not for force generation. While both neocortical and cerebellar activity increased with increasing speed and force, the speed-related changes in the cerebellum were larger than predicted by an optimized cortico-cerebellar connectivity model. We then applied the same approach in a cognitive domain, assessing how the cerebellum supports working memory. Enhanced gating was associated with the encoding of items in working memory, but not with the manipulation or retrieval of the items. Focusing on task-dependent gating of neocortical inputs to the cerebellum offers a promising approach for using fMRI to understand the specific contributions of the cerebellum to cognitive function.

Neocortical inhibitory imbalance predicts successful sensory detection.

Perceptual success depends on fast-spiking, parvalbumin-positive interneurons (FS/PVs). However, competing theories of optimal rate and correlation in pyramidal (PYR) firing make opposing predictions regarding the underlying FS/PV dynamics. We addressed this with population calcium imaging of FS/PVs and putative PYR neurons during threshold detection. In primary somatosensory and visual neocortex, a distinct PYR subset shows increased rate and spike-count correlations on detected trials ("hits"), while most show no rate change and decreased correlations. A larger fraction of FS/PVs predicts hits with either rate increases or decreases. Using computational modeling, we found that inhibitory imbalance, created by excitatory "feedback" and interactions between FS/PV pools, can account for the data. Rate-decreasing FS/PVs increase rate and correlation in a PYR subset, while rate-increasing FS/PVs reduce correlations and offset enhanced excitation in PYR neurons. These findings indicate that selection of informative PYR ensembles, through transient inhibitory imbalance, is a common motif of optimal neocortical processing.

A sensory-motor theory of the neocortex.

Recent neurophysiological and neuroanatomical studies suggest a close interaction between sensory and motor processes across the neocortex. Here, I propose that the neocortex implements active predictive coding (APC): each cortical area estimates both latent sensory states and actions (including potentially abstract actions internal to the cortex), and the cortex as a whole predicts the consequences of actions at multiple hierarchical levels. Feedback from higher areas modulates the dynamics of state and action networks in lower areas. I show how the same APC architecture can explain (1) how we recognize an object and its parts using eye movements, (2) why perception seems stable despite eye movements, (3) how we learn compositional representations, for example, part-whole hierarchies, (4) how complex actions can be planned using simpler actions, and (5) how we form episodic memories of sensory-motor experiences and learn abstract concepts such as a family tree. I postulate a mapping of the APC model to the laminar architecture of the cortex and suggest possible roles for cortico-cortical and cortico-subcortical pathways.

Hierarchical Gradients of Encoded Spatial and Sensory Information in the Neocortex Are Attenuated by Dorsal Hippocampal Lesions.

During navigation, the neocortex actively integrates learned spatial context with current sensory experience to guide behaviors. However, the relative encoding of spatial and sensorimotor information among cortical cells, and whether hippocampal feedback continues to modify these properties after learning, remains poorly understood. Thus, two-photon microscopy of male and female Thy1-GCaMP6s mice was used to longitudinally image neurons spanning superficial retrosplenial cortex and layers II-Va of primary and secondary motor cortices before and after bilateral dorsal hippocampal lesions. During behavior on a familiar cued treadmill, the locations of two obstacles were interchanged to decouple place-tuning from cue-tuning among position-correlated cells with fields at those locations. Subpopulations of place and cue cells each formed interareal gradients such that higher-level cortical regions exhibited higher fractions of place cells, whereas lower-level regions exhibited higher fractions of cue cells. Position-correlated cells in the motor cortex also formed translaminar gradients; more superficial cells were more likely to exhibit fields and were more sparsely and precisely tuned than deeper cells. After dorsal hippocampal lesions, a neural representation of the learned environment persisted, but retrosplenial cortex exhibited significantly increased cue-tuning, and, in motor cortices, both position-correlated cell recruitment and population activity at the unstable obstacle locations became more homogeneously elevated across laminae. Altogether, these results support that the hippocampus continues to modulate cortical responses in familiar environments, and the relative impact of descending feedback obeys hierarchical interareal and interlaminar gradients opposite to the flow of ascending sensory inputs.

Quantum Brain Dynamics and Virtual Reality.

In this paper we propose a control theory of manipulating holograms in Quantum Brain Dynamics (QBD) involving our subjective experiences, i.e. qualia. We begin with the Lagrangian density in QBD and extend our theory to a hierarchical model involving multiple layers covering the neocortex. We adopt reservoir computing approach or morphological computation to manipulate waveforms of holograms involving our subjective experiences. Numerical simulations performed indicate that the convergence to target waveforms of holograms is realized by external electric fields in QBD in a hierarchy. Our theory can be applied to non-invasive neuronal stimulation of the neocortex and adopted to check whether or not our brain adopts the language of holography. In case the protocol in a brain is discovered and the brain adopts the language of holography, our control theory will be applied to develop virtual reality devices by which our subjective experiences provided by the five senses in the form of qualia are manipulated non-invasively. Then, the information content of qualia might be directly transmitted into our brain without passing through sensory organs.

Top-down brain circuits for operant bradycardia.

Heart rate (HR) can be voluntarily regulated when individuals receive real-time feedback. In a rat model of HR biofeedback, the neocortex and medial forebrain bundle were stimulated as feedback and reward, respectively. The rats reduced their HR within 30 minutes, achieving a reduction of approximately 50% after 5 days of 3-hour feedback. The reduced HR persisted for at least 10 days after training while the rats exhibited anxiolytic behavior and an elevation in blood erythrocyte count. This bradycardia was prevented by inactivating anterior cingulate cortical (ACC) neurons projecting to the ventromedial thalamic nucleus (VMT). Theta-rhythm stimulation of the ACC-to-VMT pathway replicated the bradycardia. VMT neurons projected to the dorsomedial hypothalamus (DMH) and DMH neurons projected to the nucleus ambiguus, which innervates parasympathetic neurons in the heart.

Differential cortical layer engagement during seizure initiation and spread in humans.

Despite decades of research, we still do not understand how spontaneous human seizures start and spread - especially at the level of neuronal microcircuits. In this study, we used laminar arrays of micro-electrodes to simultaneously record the local field potentials and multi-unit neural activities across the six layers of the neocortex during focal seizures in humans. We found that, within the ictal onset zone, the discharges generated during a seizure consisted of current sinks and sources only within the infra-granular and granular layers. Outside of the seizure onset zone, ictal discharges reflected current flow in the supra-granular layers. Interestingly, these patterns of current flow evolved during the course of the seizure - especially outside the seizure onset zone where superficial sinks and sources extended into the deeper layers. Based on these observations, a framework describing cortical-cortical dynamics of seizures is proposed with implications for seizure localization, surgical targeting, and neuromodulation techniques to block the generation and propagation of seizures.

Layer 1 NDNF interneurons are specialized top-down master regulators of cortical circuits.

Diverse types of inhibitory interneurons (INs) impart computational power and flexibility to neocortical circuits. Whereas markers for different IN types in cortical layers 2-6 (L2-L6) have been instrumental for generating a wealth of functional insights, only the recent identification of a selective marker (neuron-derived neurotrophic factor [NDNF]) has opened comparable opportunities for INs in L1 (L1INs). However, at present we know very little about the connectivity of NDNF L1INs with other IN types, their input-output conversion, and the existence of potential NDNF L1IN subtypes. Here, we report pervasive inhibition of L2/3 INs (including parvalbumin INs and vasoactive intestinal peptide INs) by NDNF L1INs. Intersectional genetics revealed similar physiology and connectivity in the NDNF L1IN subpopulation co-expressing neuropeptide Y. Finally, NDNF L1INs prominently and selectively engage in persistent firing, a physiological hallmark disconnecting their output from the current input. Collectively, our work therefore identifies NDNF L1INs as specialized master regulators of superficial neocortex according to their pervasive top-down afferents.

Pan-cortical 2-photon mesoscopic imaging and neurobehavioral alignment in awake, behaving mice.

The flow of neural activity across the neocortex during active sensory discrimination is constrained by task-specific cognitive demands, movements, and internal states. During behavior, the brain appears to sample from a broad repertoire of activation motifs. Understanding how these patterns of local and global activity are selected in relation to both spontaneous and task-dependent behavior requires in-depth study of densely sampled activity at single neuron resolution across large regions of cortex. In a significant advance toward this goal, we developed procedures to record mesoscale 2-photon Ca2+ imaging data from two novel in vivo preparations that, between them, allow for simultaneous access to nearly all 0f the mouse dorsal and lateral neocortex. As a proof of principle, we aligned neural activity with both behavioral primitives and high-level motifs to reveal the existence of large populations of neurons that coordinated their activity across cortical areas with spontaneous changes in movement and/or arousal. The methods we detail here facilitate the identification and exploration of widespread, spatially heterogeneous neural ensembles whose activity is related to diverse aspects of behavior.

Long-wavelength traveling waves of vasomotion modulate the perfusion of cortex.

Brain arterioles are active, multicellular complexes whose diameters oscillate at ∼ 0.1 Hz. We assess the physiological impact and spatiotemporal dynamics of vaso-oscillations in the awake mouse. First, vaso-oscillations in penetrating arterioles, which source blood from pial arterioles to the capillary bed, profoundly impact perfusion throughout neocortex. The modulation in flux during resting-state activity exceeds that of stimulus-induced activity. Second, the change in perfusion through arterioles relative to the change in their diameter is weak. This implies that the capillary bed dominates the hydrodynamic resistance of brain vasculature. Lastly, the phase of vaso-oscillations evolves slowly along arterioles, with a wavelength that exceeds the span of the cortical mantle and sufficient variability to establish functional cortical areas as parcels of uniform phase. The phase-gradient supports traveling waves in either direction along both pial and penetrating arterioles. This implies that waves along penetrating arterioles can mix, but not directionally transport, interstitial fluids.

Network state transitions during cortical development.

Mammalian cortical networks are active before synaptogenesis begins in earnest, before neuronal migration is complete, and well before an animal opens its eyes and begins to actively explore its surroundings. This early activity undergoes several transformations during development. The most important of these is a transition from episodic synchronous network events, which are necessary for patterning the neocortex into functionally related modules, to desynchronized activity that is computationally more powerful and efficient. Network desynchronization is perhaps the most dramatic and abrupt developmental event in an otherwise slow and gradual process of brain maturation. In this Review, we summarize what is known about the phenomenology of developmental synchronous activity in the rodent neocortex and speculate on the mechanisms that drive its eventual desynchronization. We argue that desynchronization of network activity is a fundamental step through which the cortex transitions from passive, bottom-up detection of sensory stimuli to active sensory processing with top-down modulation.

Aging-associated weakening of the action potential in fast-spiking interneurons in the human neocortex.

Aging is associated with the slowdown of neuronal processing and cognitive performance in the brain; however, the exact cellular mechanisms behind this deterioration in humans are poorly elucidated. Recordings in human acute brain slices prepared from tissue resected during brain surgery enable the investigation of neuronal changes with age. Although neocortical fast-spiking cells are widely implicated in neuronal network activities underlying cognitive processes, they are vulnerable to neurodegeneration. Herein, we analyzed the electrical properties of 147 fast-spiking interneurons in neocortex samples resected in brain surgery from 106 patients aged 11-84 years. By studying the electrophysiological features of action potentials and passive membrane properties, we report that action potential overshoot significantly decreases and spike half-width increases with age. Moreover, the action potential maximum-rise speed (but not the repolarization speed or the afterhyperpolarization amplitude) significantly changed with age, suggesting a particular weakening of the sodium channel current generated in the soma. Cell passive membrane properties measured as the input resistance, membrane time constant, and cell capacitance remained unaffected by senescence. Thus, we conclude that the action potential in fast-spiking interneurons shows a significant weakening in the human neocortex with age. This may contribute to the deterioration of cortical functions by aging.

Prolonged Activity Deprivation Causes Pre- and Postsynaptic Compensatory Plasticity at Neocortical Excitatory Synapses.

Homeostatic plasticity stabilizes firing rates of neurons, but the pressure to restore low activity rates can significantly alter synaptic and cellular properties. Most previous studies of homeostatic readjustment to complete activity silencing in rodent forebrain have examined changes after 2 d of deprivation, but it is known that longer periods of deprivation can produce adverse effects. To better understand the mechanisms underlying these effects and to address how presynaptic as well as postsynaptic compartments change during homeostatic plasticity, we subjected mouse cortical slice cultures to a more severe 5 d deprivation paradigm. We developed and validated a computational framework to measure the number and morphology of presynaptic and postsynaptic compartments from super-resolution light microscopy images of dense cortical tissue. Using these tools, combined with electrophysiological miniature excitatory postsynaptic current measurements, and synaptic imaging at the electron microscopy level, we assessed the functional and morphological results of prolonged deprivation. Excitatory synapses were strengthened both presynaptically and postsynaptically. Surprisingly, we also observed a decrement in the density of excitatory synapses, both as measured from colocalized staining of pre- and postsynaptic proteins in tissue and from the number of dendritic spines. Overall, our results suggest that cortical networks deprived of activity progressively move toward a smaller population of stronger synapses.